BIOL 2480 - Regeneration

3 types of neuronal repair: 1) Regrowth of axons

in the PNS

Type one occurs is the axons are far enough from

the cell body in the PNS

Type one still needs contact mediated signals, NTF,

glial cells can still support growth

Type 1 is just where there is damage to an axon some distance from the cell body as it transits the PNS. Still needs same developmental pathways intact for guidance as well as

neurotrophic competition but can be clinically successful

3 types of neuronal repair: 2) Regrowth of

damaged neurons

Type 2 has more extensive damage to axons and/or dendrites but still has

intact and healthy cell body.

Type 2 Often needs repolarization of cell to reestablish

axonal and dendritic polarity

Type 2 is Often blocked by glial overgrowth and/or

inflammatory responses as well as lack of trophic support

Type 2 is very limited in

mammals

3 types of neuronal repair: 3) Genesis of

completely new neurons

Type 3 is very rare in mammals and only happens in a couple locations. Needs a population of

multipotent stem cells AND the triggers needed to start differentiation.

3.Genesis of completely new neurons, can regrow if limited cut away from

cell body

Glial overgrowth fills spaces, blocks

neurons from regrowth

Regrowth of PNS axons: Schwann cells are glial cells that produce

PNS myelin

After damage Schwann cells provide

•adhesion molecules and neurotrophins

Macrophages, around PNS, clean out cellular debris after a

cut

Fibroblasts provide a

scaffold for regrowth

Cytoskeleton components bridge the gap made by

fibroblast scaffolds

After a full cut, the intervening space forms a bridge of

Schwann cells, fibroblasts and ECM with laminins to which integrin receptors on axon can bind

Schwann cells proliferate after a cut and surround the cut region, providing

extra support

After damage Schwann cells first decrease

myelin production

Schwann cells first decrease myelin production because myelin is a

growth inhibitor

Schwann cells first decrease myelin production because myelin is a growth inhibitor, and they increase production of

laminin and fibronectin and adhesion molecules

Basal lamina of muscle stays intact for quite awhile after axotomy to maintain

synaptic site

Basal lamina of muscle stays intact for quite awhile after axotomy to maintain synaptic site and agrin signalling keeps Ach receptors clustered at

original site

Basal lamina of muscle stays intact for quite awhile after axotomy to maintain synaptic site and agrin signalling keeps Ach receptors clustered at original site. Have same activity-dependent mechanisms to keep only

one synapse stabilized in end

- if nerve to muscle basal lumina stays alive, keeps pathway in

tact, has the same attractive area, muscular side alive to support new axons

if quick cut, fibroblasts/cell body is alive

fast growth

endothelial cells, sends our growth cones, extending again and sealing gap again, either

sealing or creating pathway

CNS Damage - Brain trauma can cause neural death by

axotomy, large scale cutting of axons

After recovery you often see neurofibrillary tangles of

tau proteins

•After recovery you often see neurofibrillary tangles of tau proteins.

Can also get

astrocyte overgrowth

In healthy brains tau proteins stabilize microtubules but in damage/disease they get

disrupted

After damage, the tau proteins get tangled together, loosing

microtubular support

Chronic Traumatic Encephalopathy (CTE) is associated with

•repeated head blows.

Markers for CTE are

•Tau Protein deposition and brain shrinkage but can only be diagnosed after death

CTE has High prevalence in athletes from

contact sports

Before death, CTE can result in memory loss like Alzheimers but also

drastic behavioral changes

For CTE, it doesn't have to be a full concussion to cause damage, but has to be

repeated low level damage

Repeated accelerations and decelerations of the head can stretch

axons until they break.

After injury glial cells overgrow and can end up causing

a scar at the injury site

When tau proteins are defective, and no longer stabilize

microtubules properly, they can result in dementias such as Alzheimer's disease

CTE is a tauopathy characterized by the deposition of hyperphosphorylated tau (p‐tau) protein as

neurofibrillary tangles, astrocytic tangles and neurites in striking clusters around small blood vessels of the cortex, typically at the sulcal depths.

"Stroke" is a disruption of

•blood supply to part of the brain.

Oxidative stress can kill

neurons

Oxidative stress can kill neurons. This can lead to chain of cell death due to

•cytokines -substances released by immune cells.

Causes apoptotic cell death by blocking

anti-apoptotic gene Bcl-2, activating caspases

Bcl-2 is a gene that blocks

apoptotic pathways

Bcl-2 is a gene that blocks apoptotic pathways. When it is blocked then release o

Cytochrome C

Bcl-2 is a gene that blocks apoptotic pathways. When it is blocked then release of Cytochrome C from mitochondria with

activates caspase chain.

Define apoptosis as controlled

cell death, as opposed to necrotic

Cytokines binds when death occurs, which the Bcl2 gets

blocked, Bcl2 is the anti-apoptotic gene

the caspase pathway turns on

apoptosis

Excitotoxicity is neuronal death due to

TOO much activation.

During seizure there can be

excess glutamate release

Too much glutaminergic activity also blocks

Bcl2, same Bcl2 pathway

Autophagy is a normal response in healthy neurons to remove

damaged organelles and proteins.

Defective proteins are engulfed into phagosomes for

breakdown

Disruptions to autophagy directly contribute to neuronal cell death due to

•accumulation of toxic proteins

Disruptions to autophagy Seen in

neurodegenerative disease

Autophagy is implicated in the pathogenesis of major neurodegenerative disorders like Parkinson's, ALS and Alzheimers but it is difficult to establish a true causal link. Once proposed to be mainly an alternative cell death pathway, autophagy is now widely viewed as both a

vital homeostatic mechanism in healthy cells and as an important cytoprotective response mobilized in the face of aging

Impairment at different stages of autophagy leads to the buildup of pathogenic proteins and

Impairment at different stages of autophagy leads to the buildup of pathogenic proteins and

Damage to blood-brain barrier- is essentially a filter in

blood vessels inside brain

Endothelial cells around vessels are VERY tightly packed to

control what gets into brain

Traumatic injury that breaks this filter can let in

immune cells and cytokines

high blood pressure, has few gaps in

barrier, squeezing gaps apart

•Traumatic injury that breaks this filter can let in immune cells and cytokines, signalling the

immune response

Cytokines can activate

astrocytes and microglia to form scars

Neutrophils and other monocytes get in, causing an

autoimmune reaction

•Was thought to not exist in mammals, now more and more evidence it does.

•BrdU labels new neurons

New neurons found in

adult olfactory bulb and hippocampus

Only good evidence for adult neurogenesis is

olfactory bulb and hippocampus

Lots of interest and debate these days about it being found elsewhere but still disagreement in field if it has. Can get

neural stem cells from other areas that will turn into neurons in a dish but not for sure in a brain.

In olfactory bulb from

ventricle

In olfactory bulb from ventricle and migrate via

rostral migratory stream (RMS).

In Hippocampus from

subgranular zone (SGZ)

RMS stands for

rostral migratory stream

Stream is a tract of glial cells that form a highway and express

NCAMs.

Also heavy expression of

neuregulin along neural pathway as chemoattractant

neural stem cells, migrate from SGZ through

gyrus up to functional parts to hippocampus (memory zone in midbrain)

Hippocampus is a midbrain area critical for

•learning and memory formation

Hippocampus is split into

dentate gyrus, CA3, CA2, CA1 layers but all are connected

The subgranular zone of the dentate gyrus has

pluripotent stem cells

Hippocampus is a very active zone, needs lots of new neural connections, forming new neurons to

make connections

SGZ to DG to

CA3 to CA2 to CA1

•Hippocampus:

Type 1 neural stem cells can

becomes astrocytes

Type 2 neural stem cells can becomes

neurons or astrocytes

Astroctyes MAY influence neurogenesis via

WNT, in the hippocampus

Ventricular cells may express

Noggin

Ventricular cells may express Noggin, blocking

BMP effects in stem cells

In the SGZ, adult hippocampal progenitors are near a dense layer of granule cells that includes both mature and newborn immature neurons Within this Hippocampal astrocytes may play an important role in

SGZ neurogenesis.

this Hippocampal astrocytes may play an important role in SGZ neurogenesis. They promote the neuronal differentiation of

adult hippocampal progenitor cells.

Blockade of the Wnt signaling pathway inhibits the neurogenic activity of astrocytes in

vitro and SGZ neurogenesis in vivo

SVZ progenitors are adjacent to the ependymal cell layer of the lateral ventricles. Ependymal cells express the protein Noggin that may promote

SVZ neurogenesis by antagonizing signaling of the bone morphogenetic proteins (BMPs).

BMP causes them to remain

stem cells, stopping them from expressing a neural fate

•Olfactory bulb

Dopaminergic signalling may allow

continual proliferation

"Neurogenic niche" supports

outgrowth and differentiation

•Olfactory bulb, heavy ____ signaling here also

noggin

Neurogenesis in the Subventricular ZoneProgenitor cells (A-C) in the subventricular zone (SVZ) lie adjacent to the ependymal cell (E) layer lining the lateral ventricles and interact with

basal lamina extending from the local vasculature.

Newborn neurons reach the olfactory bulb (OB) through chain migrations and go through morphological and physiological development before integrating as

granule neurons in the granule cell layer (GCL) and as periglomerular neurons (not shown) in the glomerular layer (GL).

Mi,

mitral cell layer